8/19- Inherited Bleeding Disorders Flashcards
1
Q
What is the first step of hemostasis?
A
Injury to the endothelium allows blood to come into contact with the subendothelium
- Injury exposes tissue factor bearing cells and collagen, which VWF binds to
2
Q
VWF binds to what? Why?
A
VWF binds to collagen and tethers circulating platelets -> Platelet adhesion
3
Q
After ahesion, platelets get activated and release what?
This results in what?
A
- Thromboxane
- Serotonin
- ADP
Results in:
- Vasoconstriction
- Attract and cause platelets to stick to each other (platelet aggregation) forming a platelet plug
- Promote blood clotting
4
Q
On what factors does primary hemostasis depend?
A
Subendothelium
- Normal collagen
- Tissue factor
Von Willebrand factor
- Normal amt and function
Platelets
- Need adequate number and function
5
Q
What is secondary hemostasis?
A
The formation of insoluble, cross-linked fibrin (factor Ia) by activated clotting factors (thrombin, factor IIa)
- 2 pathways: extrinsic and intrinsic
- Stabilizes the primary platelet plug
6
Q
Clotting factors (table)
A
7
Q
Intrinsic pathway involves which factors? Extrinsic?
A
Intrinsic: 12, 11, 9, 8
Extrinsic: TF, 7
8
Q
Prothrombin to thrombin conversion depends on what coagulation factor?
A
FIIa (2a)
9
Q
Overview/organizational breakdown of inherited bleeding disorders (1’ vs. 2’)
A
Primary hemostasis
- Von Willebrand disease (VWD)
Secondary hemostasis
- Hemphilia A
- Hemophilia B
10
Q
What is the prothrombin-ase complex? What does it do?
A
Prothrombin-ase = TF + FVIIa
- Converts promthrombin to thrombin (FIIa)
11
Q
What is X-ase complex? What does it do?
A
X-ase = FVIIIa + FIXa (8 and 9)
- Activates FX (10)
12
Q
Case)
- 4 yo male with frequent nosebleeds
What do we want to know?
A
- Localized vs. systemic?
- Frequency and duration
- Onset: spontaneous vs. surgery
- Other bleeding symptoms
- Systemic dz?
- Medications: aspirin, warfarin…
- Family Hx?
13
Q
What are cinical features associated with primary hemostasis? Secondary hemostasis?
A
Primary hemostasis
- Mucosal bleeding (e.g. nosebleeds, menorrhagia, petechiae, prolonged after tooth extraction or minor oral mucosal injury)
- Bleeding with trauma/surgery
- Increased bleeding after aspirin or NSAID intake
Secondary hemostasis
- Deep bleeding (e.g. muscle, hemarthrosis, soft tissue hematoma, ecchymosis)
- Bleeding with trauma/surgery
14
Q
Which tests analyze primary hemostasis? Secondary?
A
Primary:
- Platelet count and smear review
- Platelet function analyzer (PFA-100)
- Von Willebrand panel (quantity and function)
Secondary:
- Prothrombin time (PT)
- Activated partial thromboplastin time (PTT)
- Thrombin time
- Factor activity assays
- Fibrinogen
15
Q
T/F: Factor XII deficiency is not associated with bleeding?
A
True
- Give you prolongation in PTT, but does not cause bleeding
16
Q
T/F: Factor XIII crosslinks fibrin and deficiencies may thus prolong PT or PTT
A
False
- Factor XIII crosslinks fibrin
- Deficiencies DO NOT prolong PT or PTT (but does give you bleeding)
17
Q
What is von Willebrand Disease?
A
Bleeding disorder caused by deficiency or dysfunction of vWF
- Mediates initial adhesion of platelets at sites of vascular injury
- Binds/stabilizes factor VIII (8) in the circulation
Common inherited bleeding disorder
- Prevalence = 0.6-1.3% of population
18
Q
Where is vWF made? Stored where?
A
2 cell types:
- Vascular endothelium: stored in secretory granules (Weibel-Palade bodies) from which it can be released by stress or drugs such as DDVP
- Megakaryocytes in the bone marrow, stored in platelet alpha-granules from which it is released following platelet activation
19
Q
Structure of vWF?
A
During its biosynthesis, VWF undergoes modifications that result in the production of VWF protein arranged into multimers that vary in size (small to ultra large)
- Cleared by the liver and ADAMTS13
20
Q
What are the different types of VWD?
A
Type 1: Partial quantitative deficiency of VWF
Type 2: Qualitative VWF defect (2A, 2B, 2M, 2N)
Type 3: Virtually complete deficiency of VWF
21
Q
What will the von Willebrand panel give you?
A
- Quantity (antigen)
- Function (activity)
—Ristocetin (RCoF, an antibiotic) causes platelet agglutination in the presence of VWF
- VWF Ag: RCoF ratio
- Multimers
22
Q
What is Ristocetin (RCoF)?
A
An antibiotic that causes platelet agglutination in the presence of VWF
23
Q
Type 1 VWD:
- Prevalence
- Ag/RCoF results
- Multimers
- Activity
- Risks
A
- 75% of cases
- VWF Ag and/or RCoF under 30%
- VWF Ag: RCoF ratio is normal
- Normal multimers
- 30-50% low VWF activity; risk factor for bleeding
24
Q
Type 2 VWD
- Subgroups
A
Type 2 = qualitative defects
- Low antigen +/- activity
- Abnormal VWF Ag: RCoF ratio
25
Description of **Type 2A** VWD?
Unique?
Additional testing?
Decreased VWF-dependent platelet adhesion and selective deficiency of high-molecular-weight multimers (HMWM)
- Low HMWM
- Multimers are always checked when suspect type 2 VWD
26
Description of **Type 2B** VWD?
Unique?
Additional testing?
**Increased affinity for platelet GPIb**
- Low platelets
- Low HMWM
- Ristocetin induced platelet aggregation (RIPA)
27
Description of **Type 2M** VWD?
Unique?
Additional testing?
Decreased VWF-dependent platelet adhesion without selective deficiency of HMWM
28
Description of **Type 2N** VWD?
Unique?
Additional testing?
Decreased binding affinity for FVIII (8)
- Low FVIII (8)
- Assay to determine if VWF binds to FVIII
29
Ex)
- VWF: Ag 61%
- RistoCoF: 20%
- Ratio 0.3 (low)
**Is this pt having type 1 or 2 VWD?**
- VWF \> 50% is normal
- RistoCoF of 20% is low
- Ratio 0.3 is low
So despite having some protein, it's not working very well.
- This is a **type 2** disease (decreased function)
30
Ex cont'd)
- VWF: Ag 61%
- RistoCoF: 20%
- Ratio 0.3 (low)
- Multimers: absence of HMWM
- Platelets 57,000 (nl \> 150,000)
- Factor VIII 64% (nl \> 50%)
**What disease is this?**
**Additional testing desired?**
- Presence of HMWM
- Low platelets
This is **Type 2B VWD**
Additional tests would be **RIPA** (ristocetin induced platelet aggregation)- abnormal
31
Characteristics of **Type 3 VWD**?
- Prevalence
- VWF Ag and RCoF
- Multimers?
- Very rare
- VWF Ag and/or RCoF under 5%
- Multimers are absent
32
Genetic inheritance of VWD?
Type 1: AD
Type 2A: AD (or R)
Type 2B: AD
Type 2M: AD (or R)
Type 2N: AR
Type 3: AR
**So basically, all are autosomal dominant except for 2N and 3**
33
Therapy for VWD?
Stop and prevent bleeding
**_1. Treatments that directly increase levels of VWF and FVIII_**
**- DDAVP**
- VWF/FVIII concentrate (plasma derived)
- Cryoprecipitate
**_2. Adjunctive_**
**- Antifibrinolytics**
- Hormonal therapy for girls with menorrhagia
- Avoid NSAIDs and aspirin
34
What is DDAVP?
- Synthetic analog of vasopressin
- VWF and FVIII (8) are released from endothelial cells
- Variable response
35
What are antifibrinolytics?
Antifibrinolytics: aminocaproic acid (Amicar) and Tranexamic acid (Lysteda)
- Block fibrinolysis
- Good for mucosal bleeding
- Contraindicated in hematuria or DIC
36
What is hemophilia? What clotting factors are involved?
**X-linked (recessive)** congenital bleeding disorder caused by a deficiency a specific clotting factor:
**Hemophilia A:** FVIII (8)
**Hemophilia B:** FIX (9)
37
Prevalence of Hemophilia A? B?
All ethnic groups
**Hemophilia A** is more common
- 1/5,000 live male births
- 2/3 severe
**Hemophilia B**
- 1/30,000 live male births
- 1/2 severe
38
Where is **FVIII** made? Stored?
Involved in which form of Hemophilia?
FVIII (8) is **synthesized in the liver** and by **endothelial cells** - It circulates in the bloodstream **bound to vWF**, and becomes activated at the site of vessel injury
- Hemophilia **A**
39
Where is FIX made?
Involved in which form of hemophilia?
- **Vitamin K** dependent factor
- Produced in the **liver**
- Hemophilia **B**
40
What do FVIIIa and FIXa do?
They interact cooperatively to activated FX
41
Definitions (severe, moderate, mild) for Hemophilia?
42
Again, what are common clinical manifestations of secondary hemostasis (e.g. Hemophilia)?
Repetition results in what?
Bleeding commonly into joints and soft tissues, but may occur anywhere
- Repeated joint/muscle bleeds can lead to disabling **arthritis** and muscle **fibrosis** -\> **target joint**
43
How can bleeding (in 2ndary hemostasis disorders like hemophilia) be life threatening?
**Intracranial hemorrhage**
**Iliopsoas muscle hemorrhage**
- Massive retroperitoneal bleeding with few symptoms
- Suspect in patient with lower abdominal or groin pain; prefers hip flexed and internally rotated
**Neck (retropharyngeal) hematoma**
- Airway obstruction
44
Pattern of inheritance for hemophilia?
How many de novo?
- X-linked recessive
- Up to 1/3 are spontaneous mutation
45
Genetic characteristics of Hemophilia A?
Highly heterogeneous
- Inversion, large deletions, nonsense mutations or frameshifts -\> preclude synthesis of full-length FVIII, severe hemophilia A
- Inversion intron 22, 50%
- Missense mutations -\> mild/moderate hemophilia A
46
Do female carriers of hemophilia have Sx?
They may (e.g. menorrhagia)
47
Genetic characteristics of Hemophilia B?
- Mostly **point mutations**
(missense \>\> nonsense \> silent splice \> ND)
- Deletion
48
Diagnosis of hemophilia?
- Prolonged PTT (intrinsic deficiencies)
- Normal PT
- Normal platelet count
- Assay of factor VIII or IX activity used for diagnosis and therapy
- Molecular genetic testing
49
Principles of care for hemophilia?
Primary aim is to prevent and treat bleeding with the deficient factor
- Recombinant factor product
_Comprehensive care by a multidisciplinary team:_
- Hematology MD and nurse
- Physical therapy
- Genetic counselor
- Social worker
50
How can bleeding be prevented in hemophiliacs?
**Prophylaxis with recombinant factor FVIII or FIX administered 1 to 3x/week to prevent joint damage in patients with severe hemophilia**
- FVIII half life ~ 12 hours
- FIX half life ~ 18 hours
Avoid contact sports
Avoid NSAIDS and aspirin
Helmet for young children
51
Treatment of bleeding in hemophiliacs?
Prophylaxis is not possible in all countries
On demand therapy should be given STAT if bleeding episode is suspected:
- Bleeding event and/or surgery requires frequent dosing and monitoring using factor activity assays
52
Other therapies for hemophilia
- Physical therapy
- Supportive care for joint bleeds (RICE)
- FFP and cryoprecipitate (only for hemophilia A)
- DDAVP (mild/moderate hemophilia A)
- Antifibrinolytics (Aminocaproic acid, Tranexamic acid)
53
What are some therapy-related complications in hemophilia?
- Hepatitis or HIV contaminated products before 1990
- Development of antibodies that neutralize FVIII or IX -\> Inhibitors
----Severe hemophilia A 20-30%; Severe hemophilia B 5%
----Suspect in patient with spontaneous break through bleeding despite prophylaxis
54
Case)
- 5 yo male otherwise healthy but referred for recurrent epistaxis
- Nosebleeds 2-3/mo for 10-15 min with bleeding from either nostril
- Bruises more asily than siblings
- No excessive bleeding, bruising or swelling with vaccines; no surgical challenges
- FHx: father with hemorrhage after tonsillectomy, paternal grandfather and uncles with easy brusing and frequent epistaxis
- PE: multiple bruises of varying ages on lower extremities
- CBC, PT, PTT, and fibrinogen are normal
**The most appropriate test to order next is:**
A. Bleeding time
B. Factor VIII activity
C. Factor IX activity
D. Thrombin time
E. von Willebrand panel
The most appropriate test to order next is:
A. Bleeding time
B. Factor VIII activity
C. Factor IX activity
D. Thrombin time
**E. von Willebrand panel**
55
For the last case, results are as follows:
- CBC normal with Nl Hb, Nl platelet counts
- Smear shows platelets of varying sizes with granules present - PT is 14 s (normal)
- PTT is 31 s (normal)
- Fibrinogen is 299 mg/dL (normal)
_VW panel shows:_
- FVIII = 50% (normal)
- RCoF activity = 25% (low)
- VW Ag = 35% (low)
- vWF multimers = decreased, but all types present pFA-100: collagen epi 190 s(slightly elevated)
Collagen ADP 140 s (elevated)
**Of the following, the most likely diagnosis is:**
A. Mild hemophilia A
B. Mild hemophlia A carrier
C. Type 1 VWD
D. Type 3 VWD
E. Platelet functional deficit
Of the following, the most likely diagnosis is:
A. Mild hemophilia A
B. Mild hemophlia A carrier
**C. Type 1 VWD**
D. Type 3 VWD
E. Platelet functional deficit
56
Of the following, which would be the best treatment option for this pt's bleeding Sx (i.e mild mucosal bleeding)?
A. Cryoprecipitate
B. DDAVP (intranasal), once adequate response is documented
C. Fresh frozen plasma
D. Plasma-derived factor VII product containing vWF
E. Recombinant factor VIII product
Of the following, which would be the best treatment option for this pt's bleeding Sx (i.e mild mucosal bleeding)?
A. Cryoprecipitate
**B. DDAVP (intranasal), once adequate response is documented**
C. Fresh frozen plasma
D. Plasma-derived factor VII product containing vWF
E. Recombinant factor VIII product
57
Case 2)
- 7 mo male brought to ER for inability to move L arm
- Seen by pediatrician 3 days ago for easy bruising and was sent to local hospital to have blood tests; L arm held down during venipuncture
- Sinc ethen, baby guarding arm and unable to crawl
- Afebril and other vital signs stable
- PE: multiple palpable bruises on shins and around knees
- Joint exam limited because he screams when you try to examine the L arm, but no warmth or swelling of joints
- Xray of L elbow stated that there is a joint effusion
Lab results:
- CBC normal
- PT 13.5 s (normal)
- PTT 85 s (elevated)
**Of the following the most appropriate next step in management is:**
A. Arthrocentesis (aspiration of joint fluid
B. Immobilization in cast
C. Obtain an ultrasound of the joint
D. Non-steroidal anti-inflammatory meds
E. Send STAT factor 8 and 9 levels
Of the following the most appropriate next step in management is:
A. Arthrocentesis (aspiration of joint fluid
B. Immobilization in cast
C. Obtain an ultrasound of the joint
D. Non-steroidal anti-inflammatory meds
**E. Send STAT factor 8 and 9 levels**
58
Case 2 cont'd)
- F8 under 1%
- F9 = 71%
Of the following, the best initial treatment for this pt is:
A. Aminocaproic acid
B. DDAVP
C. Fresh frozen plasma
D. Recombinant Factor 8 E. RICE and observation
Of the following, the best initial treatment for this pt is:
A. Aminocaproic acid
B. DDAVP
C. Fresh frozen plasma
**D. Recombinant Factor 8 E. RICE and observation**
59
SUMMARY of DISORDERS
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